Apparatus and method for the precise location of reaction plates

ABSTRACT

Generally, the present invention provides a device and method for accurately locating a multi-well plate at a plate-support location, e.g., a work surface, of an automated laboratory machine, such that one or more acting members of the machine, such as an array of pipette tips, optical sensors, or the like, can accurately address and operate on the individual wells. Interior and/or exterior surface regions of one or more wells of a multi-well plate are used as the primary plate features engaged by locating structure of the machine. In one particular embodiment one or more upwardly tapered projections extend from a plate-support surface of a plate-handling machine for mating engagement with the exterior surface regions of one or more wells. In another embodiment, the exterior surface regions along one or more well bottoms are engagingly received within bores, or other receiving structure, formed on the plate-support surface of a machine. In a further embodiment, one or more downwardly extending projections depend from an acting-member support, along with the acting members of a machine. Introduction of the projections into some of the wells of a multi-well plate serves to align the acting members with the plate&#39;s other wells. A biasing assembly can be used to press together the engaging surface regions of the wells and the locating structures of the machine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/010,659filed Dec. 6, 2001, which is a continuation of application Ser. No.09/321,311 filed May 27, 1999, now abandoned, which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to the positioning of multi-well plates inlaboratory machines. More particularly, the invention provides anapparatus and method for accurately locating a multi-well plate at aplate-support region of a laboratory machine, so that one or more actingmembers, e.g., an array of pipette tips or optical readers, can operateon the individual wells.

BACKGROUND OF THE INVENTION

In chemical and biological laboratories, it is often necessary toperform analytical and/or experimental assays or procedures on largenumbers of laboratory specimens. For example, a lab technician mightneed to determine the reaction of many different specimens against oneor more reagents, such as labeled probes. Common tasks that areperformed for each sample include reagent transfers (e.g., aspirationand dispensing), mixing and stirring, as well as reading the results ofeach assay.

Typically, in years past, each sample was processed in its own, separatecontainer, such as a tube or flask, in a largely manual fashion.Moreover, the early methods generally provided for the processing ofonly one or a few samples at a time and, thus, were time consuming andlabor intensive. More recently, arrays of reaction wells (e.g., 96 wellsarranged in an 8×12 array) formed in a tray or plate have become popularfor separately performing numerous reactions at substantially the sametime. Although parallel processing brought a substantial increase inthroughput, many fundamental laboratory procedures continued to becarried out in a largely manual fashion In an effort to further increasethroughput and decrease costs, many laboratory directors are now movingtoward the use of automated instrumentation, and even higher-densityplates, e.g., 384, 1536, or higher. The automation and parallelperformance of common tasks has greatly streamlined the processing ofsamples, increasing lab efficiency and eliminating many sources oferrors (e.g., technician errors).

Notwithstanding such benefits, the combination of high-density arrayformats and automated instrumentation has presented new problems thatneed to be addressed. One particularly vexing problem relates to theproper alignment of each reaction well of a multi-well plate on thesupport surface of a plate-handling machine. It should be appreciatedthat each well must be very accurately positioned in order for one ormore acting members, e.g., pipette tips or optical sensors, to addressand operate on them. For example, aligning each member of an array ofpipette tips over an array of reaction wells can be a very challengingtask. The difficulties of alignment tend to increase with the arraysize(s) involved.

Many conventional plate-handling machines locate multi-well plates byengaging the peripheral edge or sidewall of the plate against some fixedlocating feature on the instrument, such as walls or bumpers disposedalong two or more sides of a plate-support surface. Unfortunately, theposition of each well in relation to the peripheral edges or sidewallsof many plates tends to vary markedly from plate to plate, even withplates of the same model from a single manufacturer. Such variations canarise from a variety of causes. For example, current manufacturingtolerances for a plate's peripheral features are typically not veryrigorous, especially as compared to those for the wells themselves—whichcan be very exacting. Also, the relatively soft, deformable plasticsfrom which most plates are formed, e.g., polyethylene or polypropylene,can introduce dimensional variations between plates. In situations wherethe automated machinery fails to accurately align the plates, manualintervention is often required, thus significantly reducing theeffectiveness of the automation.

Clearly, there is a need for an improved apparatus and method forquickly and accurately aligning each well of a multi-well plate on theplate-support surface of a plate-handling machine.

SUMMARY OF THE INVENTION

As discussed above, prior plate-alignment techniques that rely on theouter side edges or sidewalls of a plate to position the wells areinherently unreliable, as the spatial relation between such platestructures and the various wells differ markedly from plate to plate.The present invention, on the other hand, takes advantage of the factthat the placement and dimensions of the wells themselves are typicallyquite consistent from plate to plate.

One aspect of the present invention provides an improvement for amicroplate apparatus having (i) a tray or plate defining an array ofsample wells (also referred to as a microtiter plate), (ii) aplate-handling machine having (a) a plate-support region, e g, a surfaceor deck, and (b) a sample-handling or reading device which operates onindividual wells in the plate, and (iii) a control unit for controllingthe position of the device with respect to defined coordinates (pointsof reference) on the plate-support surface. An improved plate locatingand aligning arrangement is provided, including locator structuredisposed on the plate-support surface for engaging the exterior wallsurfaces of one or more wells, when the plate is placed on theplate-support surface, so as to fix the position of each well at a knownlocation with respect to the defined coordinates.

In one embodiment, the locator structure includes at least oneprojection extending from the plate-support surface. In anotherembodiment, two or more projections (e.g., 2, 3 or 4) extend from theplate-support surface.

One or more of the projections and the exterior wall surfaces of one ormore wells can be configured with complementary shaped regions. By thisconstruction, when the plate is positioned on the plate-support surface,the complementary shaped regions can fit closely against one another. Ina particular arrangement of this type, one or more of the projectionstaper on progressing toward their upper regions (e.g., generally havinga cone shape) and one or more wells taper on progressing toward theirlower regions. The exterior wall surfaces of the tapered wells, in thisarrangement, define one or more tapered recesses, each being adapted toreceive one of the tapered projections. For example, the exterior wallsurfaces of four wells can define a recess into which a generallycone-shaped projection can fit. In another exemplary arrangement of thistype, each projection defines a central cavity (e.g., a hole or bore)that opens away from the plate-support surface. The cavity, in thisarrangement, is configured to receive a lower region of the exteriorwall surfaces of a well.

According to one embodiment, the locator structure includes no more thanone projection for every four wells of the well array, In anotherembodiment, the locator structure includes no more than one projectionfor every six wells of the well array. One particular arrangement, foruse with 96- and/or 384-well plates, includes no more than about 2-4projections on the plate-support surface for locating such a plate.

The locating and aligning arrangement of the invention can furtherinclude a biasing assembly operable, with a multi-well plate positionedon the plate-support surface, to urge the locator structure againstregions of the exterior wall surfaces of the wells. In one embodiment,the biasing assembly includes a vacuum source and a flow line forcommunicating the vacuum source with a lower side of a plate, with theplate positioned on the plate-support surface. The vacuum source, inthis embodiment, is operable to draw the plate against the plate-supportsurface. Other embodiments contemplate, for example, biasing assembliesthat are pneumatic, hydraulic, motorized, magnetic, and/orspring-loaded.

In one embodiment, the sample-handling or reading device is attached toa support. The support is adapted for movement, preferably by automatedmeans (e.g., by way of a robotic arm or cross-bar assembly, and/or amotorized carriage directed by a control unit, or the like). The movablesupport, in this embodiment, is adapted to transport the sample-handlingor reading device toward and away from a position suitable foraddressing and operating on individual wells fixed at known locationswith respect to the defined coordinates on the plate-support surface. Inanother embodiment, the sample-handling or reading device remainssubstantially stationary, and the plate-support surface is adapted formovement toward and away from a position whereat the device can operateon individual wells.

The sample-handling or reading device can include, for example, aplurality of sample-handling or reading members (also referred to hereinas acting members) disposed in an array that is alignable with at leasta portion of the well array, with the wells fixed at such knownlocations. In one embodiment, one or more of the acting members arepipette tips. In another embodiment, one or more of the acting membersare optical sensors or readers.

Another general embodiment of an improved plate locating and aligningarrangement, for use with a microplate apparatus, includes locatorstructure defined by the plate-support surface, with the locatorstructure being configured to engagingly receive a region of theexterior wall surfaces of at least one of the wells, when the plate isplaced on the plate-support surface, so as to fix the position of eachwell at a known location with respect to defined coordinates on theplate-support surface.

According to one embodiment, the locator structure is configured toengagingly receive regions of the exterior wall surfaces of at least twowells of a multi-well plate. The locator structure can include, forexample, two or more cavities (e.g., holes, bores, indentations, or thelike) defined by the plate-support surface, each cavity being configuredto receive a lower region of the exterior wall surfaces of a respectiveone of the wells.

One embodiment, wherein the locator structure comprises a cavity definedby the plate-support surface, is contemplated for use with a microtiterplate having wells with a non-circular horizontal cross-sectionalprofile. In this embodiment, the cavity has a non-circular horizontalcross-sectional profile corresponding to that of such wells. Forexample, both the cavity and the wells can be shaped as a triangle,square, rectangle, or other multi-sided shape; or as an oval, oblong orother rounded, but non-circular shape; or any combination thereof.

The locating and aligning arrangement of the invention can furtherinclude a biasing assembly operable, with a multi-well plate positionedon the plate-support surface, to urge the locator structure againstregions of the exterior wall surfaces of the wells.

In another of its aspects, the present invention provides an improvementfor a microplate apparatus having (i) a microtiter plate defining anarray of sample wells, each having interior wall surfaces, (ii) aplate-handling machine having a plate-support region, e.g., a surface,and an acting-member support with one or more sample-handling or readingmembers disposed therealong, each member being adapted to operate on anindividual well in the plate, and (iii) a control unit for controllingthe position of the support with respect to defined coordinates on theplate-support surface. An improved plate locating and aligningarrangement is provided, including locator structure depending from theacting-member support for engaging the interior wall surfaces of one ormore wells, when introduced therein, so as to fix the position of one ormore of the other wells in alignment with the sample-handling or readingmember(s).

In accordance with one embodiment, the locator structure and theinterior wall surfaces of the wells have complementary shaped regions.By this construction, when the plate is positioned on the plate-supportsurface, the complementary shaped regions can closely fit in abutmentwith one another.

The locator structure can include, for example, two or more elongateprojections (e.g., each in the nature of a pin, cone, rod, or the like)disposed in spaced relation along the acting-member support.

In one embodiment, the plate-handling machine includes a plurality ofsample-handling or reading members (also referred to herein as actingmembers). Such acting members and the locator structure, in thisembodiment, collectively define an array that is alignable with at leasta portion of the array of wells For example, two generally cone-shapedprojections, each shaped for mating engagement with the interior regionof one of the wells, can depend from spaced apart positions along thesupport. Further, an array of pipette tips, optical readers, or thelike, can also depend from the support. Together, the projections andthe acting members can define an array, such as an 8×12, 6×24, or otherarray.

The apparatus can further include a biasing assembly operable, with thelocator structure inserted into one or more wells, to urge the interiorwall surfaces of the wells and the locator structure together. Forexample, a hydraulic, pneumatic, motorized, spring-loaded or otherbiasing assembly can press a support, from which the locator or otherbiasing assembly can press a support, from which the locator structureand acting members depend, toward the plate-support surface, with theplate interposed therebetween.

These and other features and advantages of the present invention willbecome clear from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

The structure and manner of operation of the invention, together withthe further objects and advantages thereof, may best be understood byreference to the following description taken in conjunction with theaccompanying drawings, in which:

FIG. 1 is a partially schematic perspective view, from above, showingupwardly tapered pegs on a plate-support surface of a microplateapparatus, each peg being configured to engage exterior wall surfaces offour wells of a multi-well plate, when the plate is positioned on thesurface, so as to fix the position of all of the plate's wells at knownlocations on the plate-support surface, thereby permitting an array ofacting members to address and operate on the individual wells;

FIG. 2 is a top plan view showing the multi-well plate of FIG. 1 placedon the plate-support surface, with the pegs engaging the exterior wallsurfaces of respective groupings of wells;

FIG. 3 is a partial perspective view, from above, showing one of thepegs of FIG. 2 engaging the exterior wall surfaces of a respectivegrouping of wells;

FIG. 4 is a partial top view, with portions shown in phantom, of the pegof FIG. 3 engaging the exterior wall surfaces of a respective groupingof wells;

FIG. 5 is a partial top view, with portions shown in phantom, showinganother embodiment of a peg engaging the exterior wall surfaces of arespective grouping of wells;

FIG. 6 is a partial top view, with portions shown in phantom, showingstill a further embodiment of a peg engaging the exterior wall surfacesof a respective grouping of wells;

FIG. 7 is a partial perspective view, from above, showing a projectionextending from a plate-support surface, with the projection defining acavity for engagingly receiving the exterior wall surfaces of a lowerregion of a well of a multi-well plate;

FIG. 8 is a partial perspective view, from above, showing a plurality ofcavities formed in a plate-support surface, with each cavity beingconfigured to engagingly receiving the exterior wall surfaces of a lowerregion of a respective well of a multi-well plate;

FIG. 9A-9B are side elevational views, with portions shown in section,of a support with a pair of spaced-apart alignment projections dependingtherefrom, with the projections being adapted to be engagingly receivedwithin respective wells of a multi-well plate, so as to align each of aplurality of acting members, also depending from the support, with arespective well of the plate;

FIG. 10 is a perspective view, from below, showing a support member witha pair of spaced-apart alignment projections and ninety four actingmembers depending therefrom, collectively forming an 8×12 array, poisedover a 96-well plate;

FIG. 11 is a perspective view, from below, showing a support member witha four alignment projections and a linear array of acting members,poised over a multi-well plate; and

FIG. 12 is a partial perspective view, from above, showing anon-circular projection and a plurality of acting members depending froma support member, poised over a plurality of non-circular wells of amulti-well plate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an apparatus and method for accuratelylocating a multi-well plate at a plate-support location, e.g., a worksurface or deck, of an automated laboratory machine, such that one ormore acting members, such as an array of pipette tips, optical sensors,or other members, can operate on the individual wells. Features ofinterest of the plate, such as one or more wells, are used as theprimary locating structures of the plate for aligning the entire arrayof wells with respect to the machine. In preferred embodiments, forexample, the interior and/or exterior surface regions of one or morewells of a multi-well plate can be engaged by locating structure of amachine.

An exemplary microplate apparatus, indicated generally by the referencenumeral 10, is depicted in FIG. 1. In overview, apparatus 10 includes aplate (also referred to as a tray), denoted as 12, defining an array ofsample wells, such as 14, each having exterior wall surfaces 14 a. Aplate-handling machine includes (i) a plate-support region, such assurface 16, upon which plate 12 can be placed, and (ii) a movablesample-handling or reading device, shown generally at 20, having anarray of acting members 46 (e g., reagent-transfer pins), for operatingon individual wells in the plate. Locator structure 22 is provided onplate-support surface 16 for quickly and accurately locating plate 12thereon. In this embodiment, a plurality of projections 24 define thelocator structure 22, with each projection being configured as anupwardly tapered cone or peg adapted to engage the exterior wallsurfaces 14 a of a respective grouping of four adjacent wells of plate12, when the plate is positioned on the surface (FIG. 2), so as to fixthe position of all of the plate's wells at known locations with respectto defined coordinates, as at 26 a-26 e, on the plate-support surface.Once the position of each well has been fixed a control unit (C.U.) 28can effect movement of the sample-handling or reading device 20, via anysuitable moving means, relative to one or more of defined coordinates 26a-26 e, so that individual acting members of the device can address andoperate on respective wells of the plate.

The structure and operation of the present invention will now bedescribed in greater detail.

FIGS. 3 and 4 show one upwardly tapered projection 24, from theembodiment of FIGS. 1-2, mated with regions of the exterior wallsurfaces 14 a of a group of four downwardly tapered wells 14 ofmicroplate 12. The exterior wall surfaces 14 a of the four wells, alonga region central to the group, define an upwardly tapered recess orcavity in which the upwardly tapered projection is received. Preferably,the projection and the wells abut along complementary shaped regions toprovide a snug fit. By utilizing at least two such projections, matedwith respective groups of wells of the plate, the plate is effectivelyfixed or locked in place as it rests on the work surface. That is, theplate is prohibited from shifting side-to-side (lateral shifting) to anysignificant degree across the surface. Moreover, the plate is fixedagainst downward (vertical) movement, relative to the surface, by (i)permitting the well bottoms to abut the work surface and/or (ii)permitting the top region of the projection to abut the lower surface ofthe plate. Once the wells have been operated on (as by device 20 of FIG.1), the plate can be readily lifted from the work surface.

As illustrated in FIG. 1, each projection 24 can include areduced-diameter, generally cylindrical or rod-like insertion portion,as at 24 a, configured to fit snugly within a respective bore or socket,such as 16 a, provided in surface 16. The projections can be held inplace within the bores by any suitable means, e.g., frictionalengagement, snap-fitting techniques, adhesives, fasteners, welds, etc.In one preferred embodiment, between about 8-14 bores (e.g., 12) areprovided in the plate-support surface. All of the bores, in thisembodiment, are formed with substantially the same diameter and depthfor receiving projections having lower regions (e.g., like region 24 ain FIG. 1) of a given size. Two or more groups or sets of projectionsare provided, with the members of each group being of a selected,uniform size. Other than at their lower regions (i.e., the portionsadapted to fit within a bore), the projection size differs betweengroups. This arrangement is useful for accommodating a variety of platetypes/styles. For example, a user can determine (i) which group containsprojections best suited for use with a particular type of plate to beplaced on the support surface (e.g., an 8×12 well array), and (ii) whichbores on the plate support surface should receive projections from theselected group. A projection from the selected group can then be placedin each of the chosen bores. Should the user later desire to place adifferent type of plate on the surface (e.g., a 16×24 well array), anew, appropriate selection and placement of projections can be made.

The projections can be arranged in any suitable, desired pattern on theplate-support surface. In one embodiment, for example, severalprojections are clustered along a central region of the plate-supportsurface. In another embodiment, several projections are disposed atrespective points along the perimeter of the plate-support surface. Inyet a further embodiment, the projections are distributed across theplate-support surface.

The plate-support surface 16 and locator structures 24 are constructedto maintain a plate placed thereon, such as 12, in a designated locationfor a desired length of time, even under moderate stress or pressuretending to shift or otherwise laterally displace the plate from suchlocation, e.g., due to engagement with acting members of device 20, orvibratory motions caused by operation of the machine. To this end, eachof these components is preferably formed of a substantially rigidmaterial that resists bending, warping or other physical deformationunder moderate pressure, although the material may be somewhat elastic.For example, in one embodiment, the plate support surface is constructedof a suitable metal or metal alloy, such as stainless steel; and thelocator structure 22 (e.g., each projection 24) is injection molded of asturdy plastic material, such as an acrylic, polycarbonate,polypropylene, polysulfone, or the like. Preferably, movement of thesample-handling or reading device 20, relative to the plate, takes placein a substantially automated fashion, e.g., using any suitable movingmeans; although the invention can be used with manual and/or hybridarrangements (see, e.g., U.S. Pat. No. 3,568,735; incorporated herein byreference). In the embodiment of FIG. 1, device 20 is adapted formovement in three dimensions by way of an automated x,y,z-positioningassembly, indicated schematically at 30, under the direction of C.U. 28.The performance envelope of positioning assembly 30 permits movement ofdevice 20 toward, away from, and/or across (over) surface 16, asdesired. Control unit 28 can be programmed, by conventional techniques,to move the device 20 to a specific location relative to one or more ofthe defined coordinates (26 a-26 e) on the surface. Alternatively,positioning assembly 30 can be provided with a conventional visionsystem (not shown), e.g., one or more cameras or other sensing means,operatively connected to the control unit for locating coordinates onthe surface. A variety of vision systems for locating coordinate markson a work surface are known (see, e.g., U.S. Pat. No. 5,096,353,incorporated herein by reference), and suitable systems for use hereincan readily be chosen by those skilled in the art.

In one embodiment, positioning assembly 30 includes a z-motion actuatorcoupled to an x,y-shifting assembly. The z-motion actuator, in thisembodiment, is operatively connected to device 20 for moving it alongthe z direction, toward and away from a raised position. The z-motionactuator can be, for example, a hydraulic, pneumatic, or motor-drivenactuator. Several particular assemblies which can be adapted for useherein as the z-motion actuator are disclosed, for example, in U.S. Pat.Nos. 3,164,304; 3,329,964; 3,334,354; 5,306,510; 5,443,791; 5,525,515;5,551,487; 5,601,980; and 5,807,522; each of which is expresslyincorporated herein by reference. The x,y-shifting assembly, to whichthe z-motion actuator is coupled, is adapted to move the z-motionactuator linearly or in an x-y plane to locate the actuator at aselected location over the plate-support surface. Exemplary automateddevices useful for x,y shifting include, for example, robots withelectronically controlled linked or crossed movable arms, such as aSCARA, gantry and Cartesian robots. One embodiment employs a motorizedx,y-carriage or rail arrangement. In another embodiment, an arm whichsupports the z-motion actuator is threadedly mounted on a worm screwthat can be driven (rotated) in a desired direction by a stepper motor,as directed by the control unit. It is understood, of course, that anyother robotic mechanism could be used in accordance with the presentinvention so long as it can accomplish substantially the same purposesand secure substantially the same result. Several exemplary x,y-shiftingassemblies which can be readily adapted for use herein are disclosed,for example, in U.S. Pat. Nos. 5,443,791; 5,551,487; 5,306,510; and5,587,522; each of which is expressly incorporated herein by reference.

In the above-described embodiments, the plate-support surface 16 of theplate-handling machine remains substantially stationary as thesample-handling or reading device 20 is moved relative thereto. Movementof the sample-handling or reading device, however is not critical to theinvention. What is required is that the position of the sample-handlingor reading device be controllable with respect to defined coordinates onthe plate-support surface. Providing for movement of the sample-handlingor reading device is merely one way of achieving this objective. It willbe appreciated that, instead of moving the sample-handling or readingdevice, or in addition thereto, the plate-support surface can be adaptedfor movement. Any such arrangements are within the scope of the presentinvention.

As previously mentioned, FIG. 1 shows device 20 as an 8×12 array ofreagent-transfer pins depending from the lower side of a generallyplanar support, with each pin being adapted to pick up a selectedreagent from a respective well and to transfer the reagent to a selectedsubstrate. It should be noted, however, that the invention is notlimited to use with such a device. Rather, the device can be of anytype, and the nature of the particular device employed will generally bedetermined by, the application at hand Exemplary devices useful for thetransfer of liquid reagents include arrays of pipettes, quills,capillary tubes, syringes jetting devices (e.g., “sip and spit”devices), etc. Exemplary devices useful for transferring solid orsemi-solid reagents, such as micro-beads, include electrostatic and/ormagnetic pins or rods, as well as vacuum capillary tubes and the like.Instead of, or in addition to, using reagent transfer-type devices, thedevice array can include one or more sensors and/or readers.

From the foregoing, it will now be appreciated that a wide variety ofcommercially available robotic workstations can be readily adapted forpracticing the invention. In particularly suitable workstations, (i) theposition of one or more pipette tips, sensors, or other acting members,can be controlled with respect to selected points in space over aplate-support surface (preferably within about 0.2-0.3 mm repeatability)and (ii) the locator structure described herein can be accommodatedeither natively, or by modification/retro-fit. Commercially availableworkstations and robotic assemblies, contemplated for use with thepresent invention, include, for example: the TOMTEC QUADRA96 orQUADRA384 Series of Automatic Pipetters, and/or the TECAN GENESIS Seriesof Robotic Sample Processors (RSP's). Other commercially availablerobotic assemblies, suitable for use herein are described, for example,in U.S. Pat. No. 5,366,896, which is expressly incorporated herein byreference.

Additional details pertaining to the locator structure 22 will now bedescribed.

Where projections 24 having a substantially circular horizontalcross-section are employed, as shown in FIGS. 1 through 4, the locatorstructure 22 will typically include more than one such projection inorder to prevent pivotal movement of the plate on the surface. Thus, atleast two such projections (e.g., four, as shown in FIGS. 1 and 2) arepreferably used to fix the position of plate 12 on surface 16. It shouldbe appreciated that a projection need not engage each and every well ofa multi-well plate in this embodiment, nor most of the wells. In thisregard, it is preferred that the locator structure includes no more thanone projection for every four to six wells, or so, of the plate. Theembodiment of FIGS. 1-2, for example, provides only one projection forevery 24 wells of the plate (i.e., four projections for a 96-wellplate).

In another embodiment, locator structure 22 includes a cavity that opensaway from the plate support surface and in which the lower region of arespective well can be received. For example, FIG. 7 shows a cavity 324with an axial bore 40 extending downwardly from its top region, definingthe cavity for engagingly receiving the lower region of the exteriorwall surfaces 14 a of a respective well 14. Where the cavities and wellsare generally circular in horizontal cross-section, as in FIG. 7, atleast two (e.g., four) such projections/cavities are preferablyprovided. Where the wells and cavities have a non-circularcross-section, on the other hand, one such cavity can be sufficient tofix the position of a plate. For example, a cavity and a mating well canbe shaped as a triangle, square, rectangle, or other multi-sided shape;or as an oval, oblong or other rounded, but non-circular, shape. Ifdesired, a plurality of such non-circular cavities (e.g., 2, 4 or 6) canbe employed. Irrespective of each cavity's cross-sectional profile, theinterior surface regions of each cavity are preferably configured tocomplement the exterior surface regions the wells.

In a related embodiment, the locator structure 22 includes one or morecavities defined by the plate-support surface itself. For example, oneor more cavities (e.g., holes, bores, or the like), such as at 140 inFIG. 8, can be formed in the plate-support surface, with each cavitybeing configured to engagingly receive a lower region of the exteriorwall surfaces 14 a of a respective well 14.

In another embodiment, the locator structure 22 is associated with thestructure supporting the acting members (e.g., pipettes, opticalreaders, etc.) of a machine. For example, one or more downwardlyextending projections can depend from an acting-member support, alongwith the acting members of a machine. Introduction of the projectionsinto some of the wells of a multi-well plate serves to align the actingmembers with the plate's other wells. Preferably, the projections andthe interior wall surfaces of the wells have complementary shapedregions. By this construction, when the plate is positioned on theplate-support surface, the complementary shaped regions can closely fitin abutment with one another.

In an exemplary arrangement of this type, illustrated in FIGS. 9A-9B, asample-handling or reading device 20 includes a support portion 42operably connected to an x,y,z-positioning assembly, shown in part at30. The locator structure, in this embodiment, includes a pair ofelongate projections 44 (e.g., each in the nature of a pin, cone, rod,or the like) disposed in spaced relation along support 42. In additionto the projections any, array of acting members, such as 46, also dependfrom the support As the support is lowered from a position above plate12 (FIG. 9A) to a position whereat each projection 44 becomes seatedwithin a respective well 14 (FIG. 9B), proper alignment of each actingmember with a respective well is ensured. As best seen in FIG. 9B, thecircumferential regions of each projection fit snugly against theinterior wall surfaces 14 b of a respective well. Each projection ispreferably provided with a tapered lower region to assist in bringingthe plate into alignment as the support is lowered.

Any reasonable number of projections can depend from the support, aswell as any number of acting members. Several exemplary arrangements areshown in FIGS. 10-12. FIG. 10 for example, shows a movable support 142having two projections 44 and ninety four acting members 46. Together,the projections 44 and acting members 46 define an 8×12 array, with theprojections disposed at diagonally opposed corner regions of the array.Preferably, the array is configured to be alignable with the wells of astandard 96-well plate 12. FIG. 11 shows twelve acting members 46disposed at respective positions along a movable support 242 so as todefine a linear array. Similar to the previous arrangement, the actingmembers are spaced about 9 mm center-to-center, to be alignable with12-well rows of a standard 96-well plate 12. A projection 44 is disposedat each corner of the support, for assisting in such alignment. Thealignment can be readily effected by inserting any two or more of theprojections into respective wells of the plate. FIG. 12 shows a movablesupport 342 with a single, non-circular (square) projection 144depending therefrom, as well as an array of acting members 46.Projection 144 is configured to fit snugly within a well 114 of plate112. Notably, the well has a non-circular horizontal cross-sectionsubstantially like that of the projection. While only one projection isshown in FIG. 12, it should be appreciated that additional projectionscan be utilized, if desired.

In general, it should be appreciated that the locator structure 22 ofthe present invention can be configured with any reasonable shape,depending upon the specific shape(s) of the mating feature on the plate.Any of the embodiments taught herein can further include a biasingassembly 34 operable, with a multi-well plate positioned on theplate-support surface, to urge the locator structure against the wallsurfaces of the wells. This can be useful to encourage a close fitbetween the locator structure and such plate features. With regard tothe force applied, one embodiment contemplates a delta of approximately3 psi. For a 3″×5″ plate, for example, about 45 lbs total force iscontemplated. In one embodiment, particularly useful with thearrangements of FIGS. 1-8, the biasing assembly 34 includes a vacuumsource 35 and a flow line 36 for communicating the vacuum source 35 witha lower side of a plate, with the plate positioned on the plate-supportsurface. The vacuum source 35, in this embodiment, is operable to drawthe plate toward the plate-support surface. Other embodimentscontemplate, for example, biasing assemblies that are pneumatic,hydraulic, motorized, and/or spring-loaded. In one embodiment, az-motion actuator acts as a biasing assembly 34 for pressing the platetoward the plate-support surface. Positioning assembly 30, of FIGS.9A-9B, for example, can be used to press the movable support 42, fromwhich the locator structure 44 and acting members 46 depend, toward theplate-support surface (upon which the plate sits), with the plate 12interposed therebetween.

One embodiment contemplates, in addition to the previously describedlocator structure 22, one or more walls or bumpers (not shown) disposedalong the perimeter of the plate-support surface. Such additionalstructure is preferably configured to engage the peripheral edges orsidewalls of the plate as the plate is initially being placed on thework surface, thereby effecting a gross alignment of the plate withrespect to the work surface. Such gross alignment can be useful forquickly positioning particular groupings of wells, e.g., thosepositioned about the crosses shown on the upper surface of plate 12 inFIG. 1, over respective pegs disposed on the plate, as indicated by thedrop-down dotted lines. Once grossly aligned in this fashion, the wellsare then finely aligned as the exterior wall surfaces of the wellsengage the pegs, as previously described.

It is noted that the present invention can be readily adapted toaccommodate microtiter plates of virtually any size and having wellsdisposed in any layout. The particular plates used will, of course, belargely determined by the laboratory machine, or machines, and thenature of the assays (e.g., types of reagents) at hand. Although theillustrated embodiments show arrangements configured in accordance withthe popular 96-well format, the invention also contemplates any otherreasonable number of wells (e.g., 12, 24, 48, 384, etc.) disposed in anysuitable configuration.

It will be appreciated that the present invention can be used for theprecise and accurate location of reaction plates on a wide variety ofwork surfaces, instruments and robotic manipulators. Among theseinclude, for example, plate-handling robots, automatic pipetters,nucleic acid (e.g., RNA or DNA) sequencers, processor work surfaces,detector stages, polymerase chain reaction (PCR) thermal cyclers, etc.In one embodiment, the invention is used with a 384-well pipettor and PEBiosystems 3700.

It will further be appreciated that the present invention offers manyadvantages over the known positioning techniques. For example, thelocation of the reaction plates is as precise as the features ofinterest. Further, reaction plates made from soft or flexible materialcan be easily handled and accurately positioned. It will be appreciatedthat the present invention is adaptable to a wide variety of laboratoryapparatuses, without loss of precision. Advantageously, the presentinvention does not require modification to existing or availablereaction plates, nor attachment of any adapter(s).

Those skilled in the art can now appreciate from the foregoingdescription that the broad teachings of the present invention can beimplemented in a variety of forms. Therefore, while this invention hasbeen described in connection with particular embodiments and examplesthereof, the true scope of the invention should not be so limited.Various changes and modification may be made without departing from thescope of the invention, as defined by the appended claims.

1. A microplate apparatus comprising: a microplate defining an array ofat least 1536 wells; a plate-handling machine having a plate-supportsurface and a liquid-handling device; wherein said liquid-handlingdevice includes at least 96 acting members, with said acting membersbeing disposed in an array that is alignable with at least a portion ofthe well array; a control unit for controlling the position of saidliquid-handling device with respect to defined coordinates on saidplate-support surface; a locator structure adapted to engage at least aportion of an exterior surface of said microplate when the plate ispositioned on said plate-support surface, to fix the position of eachwell at a known location with respect to said defined coordinates; and abiasing assembly operable, with said microplate positioned on theplate-support surface, to urge the locator structure against saidexterior wall surface.
 2. The apparatus of claim 1, wherein saidliquid-handling device includes at least 384 acting members.
 3. Theapparatus of claim 1, wherein said biasing assembly includes a vacuumsource and a flow line for communicating the vacuum source with a lowerside of said plate.
 4. The apparatus of claim 1, wherein said plate is a3″×5″ plate.
 5. The apparatus of claim 1, wherein said acting memberscomprise reagent-transfer pins.